DESCRIPTION (application abstract): Since the cerebellum develops over a considerable period of time, it is vulnerable to a wide range of genetic, environmental and pharmaceutical perturbants. It is also increasingly clear that the cerebellum participates in both motor and cognitive learning; therefore cerebellar defects can underlie or participate in a wide range of developmental brain disorders including fetal alcohol syndrome, seizures due to brain malformations, hereditary cerebellar degenerations, infantile autism, ataxia telangiactasia, and possibly dyslexia. Because of the extended developmental and plastic time-period, it may also be feasible to treat such disorders by enhancing cell outgrowth during infancy and early childhood. However, more knowledge of both the cellular factors that influence cerebellar development, and optimal methods for altering these will be required, The long-term goal of this project is to establish methods to manipulate the cerebellum genetically. This will require both knowledge of the hierarchy of gene expression, and a capacity to deliver and control gene therapies. Experiments in this proposal will encompass both the underlying developmental neurobiology and vector technology to manipulate the genes. initial experiments will test a feline lentivirus as a transfer vector, under circumstances where quantitative parameters of success are available. The mouse mutant staggerer (sg) will be used as a model system, since it shows a well-characterized defective cerebellar development, the gene has been cloned, and many of its morphological, genetic and biochemical effects are already known. The system can then be used to optimize cellspecific promoters and vector targeting strategies. Once this assay system is in place for one vector, it can also be used to test modifications of vector specificity and expression, as well as additional vectors such as AAV complexes.